Semantic Deficits in Temporal Lobe Epilepsy Surgical Patients may represent a Structural Connectivity Problem: Exploration with Diffusion Imaging Abstract Semantic memory reflects one's knowledge of factual information about the world and one's experiences, while semantic processing more broadly relates to the act of accessing this stored knowledge. Although a great deal has been learned about semantic processing from both lesion studies and neuroimaging paradigms, great uncertainty remains regarding the neural mechanisms involved in these processes and the representation of conceptual information in the brain. Our research with temporal lobe epilepsy (TLE) surgical patients demonstrates that language dominant anterior temporal lobe (ATL) dysfunction is associated with category-related naming problems while nondominant ATL dysfunction is associated with category-related deficits in visual recognition and familiarity judgments. Category-related deficits are frequently present preoperatively in TLE patients, and worsen dramatically in many patients following surgery. Our data suggests nearly all adult onset TLE patients exhibit such declines while many of the early onset patients do not (likely reflecting reorganization of function in the latter group). Preliminary data indicate that some patients experience significant compromise of vocational and/or social functioning due to these limitations;with many experiencing concomitant emotional/psychiatric distress. Nevertheless, these deficits have gone virtually unrecognized by the epilepsy surgical community. Our data indicate that these naming, recognition, and familiarity deficits reflect "disconnection syndromes," as core components of functioning (e.g., language, visual processing, semantic knowledge) appear intact despite task failures occurring when our measures require interaction between them. We also present several different examples demonstrating that altering task demands can facilitate or hinder performance. For example, patients with naming deficits typically select the correct object name when provided with a multiple choice recognition format, yet are again unable to spontaneously name the same visual image presented only minutes later. Research demonstrates that neural regions in the ATL and the white matter (WM) pathways that connect them to other key brain areas underlie our ability to recognize and name certain object categories. As diffusion tensor imaging (DTI) and subcortical electrostimulation mapping of the WM suggest that damage to these tracts is sufficient to cause recognition and naming deficits, we believe that the disruption of these WM tracts (due to physiological changes related to seizures preoperatively or surgical transection) contributes to these deficits in TLE patients. Therefore, we propose using DTI to determine the relationship between category-related naming and visual recognition performance and WM pathways that lie at the core of the neural circuits that subsume these processes. If we can identify the critical WM pathways, in the future it can be ensured that these are spared by the neurosurgeon by altering surgical approach or using alternative techniques (e.g., Gamma Knife, responsive stimulation mapping), thus preventing devastating deficits in naming, recognition of faces/objects, and complex semantic learning. We will demonstrate the key pathways by establishing which tracts that traverse the TL regions of each cerebral hemisphere are strongly correlated with baseline performance, and by examining which are compromised when category-related deficits are observed. Our study represents an important step towards understanding these circuits, and will allow us to create preoperative "diffusion imaging maps" to guide surgical intervention in conjunction with stealth technology or intraoperative MRI for patients undergoing surgery involving the anterior TLs. This is consistent with the NIH Curing Epilepsy goal of improving the clinical outcome of epilepsy patients, and has broader implications for patients undergoing other neurosurgical interventions and diseases of the TLs. In subsequent studies we hope to combine diffusion imaging techniques with functional connectivity paradigms in order to study the broader neural circuits involved in supporting these cognitive functions. The current K02 award mechanism will provide Dr. Drane with the necessary training to effectively analyze the data obtained with these neuroimaging tools, while further determining the contribution of WM to these cognitive skills. We feel it is imperative for a clinical researcher to be skilled in these advanced diffusion imaging techniques (given their absence in most clinical settings) in order to insure that this procedure gets validated at the level of the individual, and translated into regular clinical use. We also hope that this project will allow us to turn our research protocol into a clinical measure of category-related naming and recognition performance that can be disseminated throughout the epilepsy surgical community, as no measures of this type are currently available. Finally, our research also has intrinsic value to neuroscience, as we can make great strides in mapping the neural circuitry of the semantic memory system in a manner that is not possible in healthy controls or patients with other neurological diseases.